Hyperglycemia and insulin resistance are common in many metabolic disorders such Type 2 diabetes, obesity, and metabolic syndrome. In these chronic conditions, there is a decreased responsiveness to endogenous insulin (insulin resistance). The decreased responsiveness to insulin results in a reduction in insulin- regulated glucose disposal, which occurs mostly in skeletal muscle. Acute insulin resistance and hyperglycemia are much less studied, but are characteristic metabolic responses to infections and injuries such as surgery, burns, trauma and hemorrhage. Recent data suggests that intensive insulin treatment of ICU patients may reduce both morbidity and mortality associated with critical illness. However, there is some controversy concerning the proper use of intensive insulin therapy, and under what conditions it can do the most good, or conversely when it is unnecessary or harmful. Intensive insulin therapy increases the likelihood of deleterious hypoglycemic incidents, a major complication of intensive insulin therapy. Even though intensive insulin therapy is now extensively used in the ICU, little is known about the mechanisms underlying the acute onset of insulin resistance. For instance, how quickly it develops, what are the causative factors, what intracellular signaling pathways are affected, and what tissues are involved. An understanding of how this insulin resistance develops will be important in determining the proper application of intensive insulin therapy, the most advantageous time for initiation following different injuries, and may suggest new treatment protocols to increase survival of critically ill patients. For instance, is therapy to reuce insulin resistance more advantageous to the patient than intensive insulin therapy? And what tissue or tissues need to be targeted? Insulin resistance can be explained by changes in the number of insulin receptors or their activity, or a post- receptor defect. Our recently published and preliminary data indicate that there are insulin receptors and post-receptor defects in insulin signaling that develop in skeletal muscle following surgical trauma and hemorrhage. The data suggests an important role for the glucocorticoids and proinflammatory cytokines, but how they interact to cause the initial development of insulin resistance is unknown. Additional preliminary data indicate that the mechanisms of the development of insulin resistance are different in the three main insulin target tissues, skeletal muscle, liver, and adipose tissue. This makes it necessary to study each tissue separately, to determine how this insulin resistance occurs. In addition, there are time-dependent changes in the factors that maintain the insulin resistant state. We have also found these to be tissue dependent. These results may be clinically advantageous, allowing us to specifically target individual tissues with treatments less likely tha intensive insulin therapy to cause hypoglycemic incidents, and more likely to achieve the proper range of blood glucose levels in patients in the ICU. Thus, studies are proposed in this application to determine the mechanism(s) of the development of acute insulin resistance in skeletal muscle. Also, much of this application is designed to study the mechanisms of recovery of insulin sensitivity following resuscitation. Potential clinical treatments are explored that may work to reverse the mortality and morbidity related to hyperglycemia and insulin resistance in the critical care setting following injury, infection and critical illness.